Lung cancer is the leading cause of cancer mortality in the United States and non-small cell lung cancei (NSCLC) represents 80% of all lung cancers. Along with tobacco use, exposure to radon, occupational exposures, exposure to asbestos, diet and family history all contribute to an increase in the risk of lung cancer. Thus, NSCLC represents a significant public health issue. Ninety percent of the deaths associated with NSCLC can be attributed to metastasis. Recent data has identified several genes associated with metastasis. However, no one has taken a global genomic approach to the analysis of molecular changes associated with metastasis in NSCLC. The goal of this project is to establish models of NSCLC invasion and metastasis, there identify changes in gene expression which correlate with enhanced invasion and metastatic potential of cancei cells. We will establish cell lines from which we can directly compare gene expression profiles between 1) cells with an increased metastatic capability, and 2) cells with an increased invasive capability with the parent cell lines from which these cells are derived. Aim 1 select NSCLC cells with enhanced invasion capacity from immortalized human primary NSCLC cell lines. Aim 2 will establish in vivo models of NSCLC metastasis by orthotopic injection of immortalized human primary NSCLC cell lines into the lungs of mice. Gene expressior profiles will then be obtained from cells derived in both aims using DNA microarray technology. Once genes are identified that are altered in metastasis compared to the primary tumor, future studies will focus on the role of gene products in the metastatic process. Our focus will be on examining changes in expression of genes associated with regulation of cytoskeleton dynamics, but this global strategy will allow us to identify other genes important in the metastatic process. This project will lead to additional research addressing important questions in molecular and cellular biology of metastases from a multidisciplinary point of view by fostering collaboration between Dr. Lader (the PI), Dr. Kwiatkowski, an expert in genetics and molecular biology, and are an expert in metastasis.